Three major processes could be involved in the pathogenesis of obesity: (1) excess deposition of lipids in adipocytes, (2) reduction of lipid mobilization from adipocytes and (3) decreased lipid utilization.
Until recently, the only factor known to cause excess deposition of fat was a positive energy balance from excess energy intake. Primary adipocyte hyperplasia or increase in enzymes involved in lipogenesis does not play a role in human obesity. (E. L. Bierman and J. Hirsch, Obesity In: R. H. Williams, ed., Textbook of Endocrinology, 6th Ed., Philadelphia, Pa., W. B. Saunders Co., 907-921, 1981). Furthermore, there is no evidence that reductions in lipid mobilization occur. However, decreased lipid utilization is attributable to both reduced physical activity and defective thermogenesis, involving inactivity in children (S. B. Roberts, J. Savage, W. A. Coward, B. Chen and A. Lucas, Energy Expenditure: An Intake in Infants Born to Lean and Overweight Mothers, N. Engl. J. Med., 318:461-466, 1988) and heredity in adults. (E. Ravussin, S. Lillioja, W. C. Knowler et al., Reduced Rate of Energy Expenditure as a Risk Factor for Body Weight Gain, N. Engl. J. Med., 318:467-472, 1988)
Among Pima Indians, Ravussin et al. supra, showed that inherited differences in expenditure of energy contribute importantly to the development of obesity. A difference in basal energy expenditure of 298 Joules per day (J/d) can lead to a mean weight gain of 15.7 kg over 622 days, representing 34% of the total positive energy balance.
Bouchard and coworkers (C. Bouchard, A. Tremblay, J. P. Despres et al., The Response to Long-Term Overfeeding in Identical Twins, N. Engl. J. Med., 322:1477-1482, 1990) studied the response to long-term overfeeding in 12 pairs of identical twins fed an excess of 4200 J/d (6 days per week) for 84 days. The variance between twin pairs was three times greater than within twin pairs. Thus, genetic factors in twins regulate energy storage and energy expenditure.
Stunkard et al. (A. J. Stunkard, J. R. Harris, N. L. Pedersen and G. E. McClearn, The Body-Mass Index of Twins Who have been Reared Apart, N. Engl. J. Med., 322:1483-1487, 1990; A. J. Stunkard, T. I. A. Sorensen, C. Hanis et al., An Adoption Study of Human Obesity, N. Engl. J. Med., 314:193-198, 1986) examined the body mass of 93 identical twin pairs reared separately and 184 pairs reared together. That investigation established that genetic influences on body mass indices in adults are substantial, whereas the childhood environment has little or no influence.
About 1% to 2% of obesity can be ascribed to lesions in hypothalamic appetite regulatory centers, of which the paraventricular nucleus is the most important. The causes of hypothalamic obesity, as reported by Bray and Gallagher, (G. A. Bray and T. F. Gallagher, Manifestations of Hypothalamic Obesity in Man: A Comprehensive Investigation of Eight Patients and a Review of the Literature, Medicine, 54:301-330, 1975) include trauma, adenomas of the third ventricle, inflammatory processes, craniopharyngioma and aneurysms of the internal carotid. Hypothalamic obesity was characterized by sudden-onset hyperphagia and was not due to alterations in energy expenditure, lipolysis, or endocrinopathies.
To understand potential hypothalamic causes of obesity, regulation of normal appetite must be considered. It has been established that the assimilation of nutrients is regulated by a homeostatic system involving both acute and chronic components. Meal size, frequency, and composition are regulated acutely by peripheral elements, including taste perception; by gastric and gastrointestinal satiety factors; and by the hypothalamus, which integrates hormonal, thermal, metabolic and neurogenic signals. Neural regulation occurs in the lateral perifornical region, where .beta.-adrenergic stimuli inhibit eating.
The most important appetite-inhibiting neuropeptides until this invention include corticotropin releasing hormone, calcitonin gene-related peptide and neurotensin. Generally such neuropeptides will not find general applicability because of the many untoward side effects resulting from the normal primary activities of the neuropeptides.
In addition to peptides, neurotransmitter substances, the most important of which are dopamine and serotonin, can play an inhibitory role in appetite regulation.
A number of peptides stimulate eating, for example, those of the homologous neuropeptide Y family, including neuropeptide Y, neuropeptide YY, and pancreatic polypeptide.
Over longer time intervals, humoral substances, particularly insulin, may participate in the regulation of total body fat mass in the central nervous system. (D. Porte and S. Woods, Regulation of Food Intake and Body Weight by Insulin, Diabetologia., 20:274-280, 1981). This is important because plasma insulin concentrations are correlated precisely and positively with total body fat and are in equilibrium with spinal fluid insulin. Thus, insulin could serve as a central nervous system humoral monitor of total body fat.
Because weight in a given individual appears to vary minimally above and below narrow limits, Keesey (R. E. Keesey, The Body-Weight Set Point: What Can You Tell Your Patients?, Postgrad. Med., 83:114-118, 1988) put forward the concept of a "physiological set point" that controls energy expenditure. It is not known whether such a set point is relevant to human weight regulation. However, animals fed diets with excessive or deficient energy tend to return to their control weights after such diets are terminated. (I. L. Bernstein, E. C. Lotter, P. J. Kulkosky, D. Porte and S. C. Woods, Effects of Force-Feeding Upon Basal Insulin of Rats, Proc. Soc. Exp. Biol. Med., 150:546-548, 1975).
Treating obesity is exceedingly difficult; permanent reversal of obesity is achieved in fewer than 10% of patients after 10 years.
Attaining a negative energy balance is central to the successful management of obesity. Moreover, energy units are equivalent whether they are derived from macronutrient protein, fat, carbohydrate or ethanol. The most appropriate diet for the obese patient is a balanced diet approximating 3600 to 4200 J/d to achieve gradual weight reduction. Very-low-energy diets (&lt;1600 J/d) or total starvation diets are not generally useful, although the previously associated serious or fatal complications are now rarely encountered.
Since 14,700 J equals 0.45 kg of body weight, a negative energy balance of 2100 J/d can achieve a weight loss of approximately 0.45 kg/wk.
Weight loss achieved by diet involves loss of lean body mass (muscle and bone) as well as fat. Thus, because obese individuals are prone to recurrent weight gain, they tend to develop a progressively disproportionate amount of fat in their body composition. Frequent smaller feedings of isoenergy diets, however, do promote weight loss, because consumption of large, intermittent food masses exacerbates abnormal patterns of excessive eating.
A good mechanism for promoting energy expenditure physiologically is by increasing physical activity. Exercise alone, however, is not an efficient means of weight loss, since small amounts of food intake can reverse gains achieved through exercise. Exercise must always be supplemented by diet and, optimally, behavioral modification. Anorexigenic medications also are helpful occasionally.
Drugs have a limited but definite role in combination with the therapies described above. The most useful include the catecholamine congeners diethylpropion hydrochloride (Tenuate, Marion Merrell Dow Pharmaceutical Co., Cincinnati, Ohio), mazindol (Mazanor, Wyeth-Ayerst Laboratories, Philadelphia, Pa.) and phentermine resin (Ionamin, Pennwalt Corp., Rochester, N.Y.); and the indolamine, fenfluramine hydrochloride (Pondimin, AH Robins Co., Richmond, Va.). A large study by the Food and Drug Administration demonstrated that drug therapy can achieve a weight loss of 0.22 kg/wk greater than that with diet alone. (A. C. Sullivan and K. Comai, Pharmacological Treatment of Obesity, Int. J. Obes., 2:167-189, 1978)
Cyclo (His-Pro) (histidyl-proline diketopiperazine) is a cyclic dipeptide derived by limited proteolysis of thyrotropin-releasing hormone (TRH, pGlu-His-ProNH.sub.2) through the action of the brain enzyme pyroglutamyl peptidase (C. Prasad and A. Peterkofsky, Demonstration of Two Separate Enzymatic Activities for the Degradation of Thyrotropin-Releasing Hormone in Hamster Hypothalamic Extracts, J. Biol. Chem, 251:3229-3234, 1976; C. Prasad, T. Matsui and A. Peterkofsky, Antagonism of Ethanol Narcosis by Histidyl-Proline Diketopiperazine, Nature, Lond., 268:142-144, 1977).
Since discovery of cyclo (His-Pro) in 1976, the cyclic dipeptide has been shown to elicit a number of endocrine and central nervous system-related biological activities including: (1) elevation of brain cGMP levels (T. Yanagisawa, C. Prasad, J. Williams and A. Peterkofsky, Antagonism of Ethanol-Induced Decrease in Rat Brain cGMP Concentration by Histidyl-Proline Diketopiperazine, A Thyrotropin-Releasing Hormone Metabolite, Biochem. Biophys. Res. Commun., 86:1146-1153, 1979); (2) attenuation of ethanol-induced sleep (C. Prasad et al. (1977) supra); (3) decrease in food intake (J. E. Morley, A. S. Levine and C. Prasad, Histidyl-Proline Diketopiperazine Decreases Food Intake in Rats, Brain Res., 210:465-478, 1981); (4) hypothermia in rats (C. Prasad, T. Matsui, J. Williams and A. Peterkofsky, Thermoregulation in Rats: Opposing Effects of Thyrotropin-Releasing Hormone and its Metabolite Histidyl-Proline Diketopiperazine, Biochem. Biophys. Res. Commun., 85:1582-1587, 1978); (5) attenuation of ketamine-induced anesthesia (H. Bhargava, Antagonism of Ketamine-Induced Anesthesia and Hypothermia by TRH and Cyclo (His-Pro), Neuropharmacology, 20:699-702, 1981); (6) inhibition of dopamine uptake by rat brain striatal synaptosomes (F. Battaini and A. Peterkofsky, Histidyl-Proline Diketopiperazine; An Endogenous Brain Peptide that Inhibits Na.sup.+ /K.sup.+ ATPase, Biochem. Biophys. Res. Commun., 94:240-247, 1980); and (7) inhibition of prolactin secretion in vitro (K. Bauer, K. J. Graf, A. Faivre-Bauman, S. Beier, A. Tixier-Vidal and H. Kleinhauf, Inhibition of Prolactin Secretion by Histidyl-Proline Diketopiperazine, Nature, 274:174-175, 1978; S. Melmed, H. E. Carlson, R. Rand and J. M. Hershman, Histidyl-Proline Diketopiperazine Suppresses Prolactin Secretion in a Human Pituitary Cell Line, Endocrinology, 106:699A, 1980; C. Prasad, J. F. Wilber, V. Akerstrom and A. Banerji, Cyclo (His-Pro): A Selective Inhibitor of Rat Prolactin Secretion In Vivo, Life Sci., 27:1979-1983, 1980).
A number of the biological activities associated with cyclo (His-Pro) are similar to those of TRH (H. Bhargava et al. (1981) supra; R. L. Gebhard, J. E. Morley, W. F. Prigge, M. W. Goodman and C. Prasad, TRH and Histidyl-Proline Diketopiperazine Inhibit Cholesterol Synthesis in Dog Intestine, Peptides 2:137-140, 1981; J. E. Morley et al. (1981) supra; Co Prasad et al. (1977) supra; and T. Yanagisawa et al. (1979) supra) whereas other activities either are opposite to those of TRH (K. Bauer et al. (1978) supra; S. Melmed et al. (1980) supra; C. Prasad et al. (1978) supra; and C. Prasad et al. (1980) supra) or completely unrelated to those of TRH (F. Battaini and A. Peterkofsky (1980) supra). In addition there are known TRH-related biological functions that are unique to TRH and cyclo (His-Pro) has not been shown to possess the ability to effect those functions (C. Prasad et al. (1977) supra and C. Prasad et al. (1980) supra).